CD8+ Cytotoxic T Lymphocyte Activation by Soluble Major Histocompatibility Complex-Peptide Dimers
Marek CebecauerPhilippe GuillaumeSilke MarkOlivier MichielinNicole BoucheronMichael BezardBruno MeyerJean‐Manuel SeguraHorst VogelImmanuel F. Luescher
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Abstract:
CD8+ cytotoxic T lymphocyte (CTL) can recognize and kill target cells that express only a few cognate major histocompatibility complex class I-peptide (pMHC) complexes. To better understand the molecular basis of this sensitive recognition process, we studied dimeric pMHC complexes containing linkers of different lengths. Although dimers containing short (10-30-A) linkers efficiently bound to and triggered intracellular calcium mobilization and phosphorylation in cloned CTL, dimers containing long linkers (> or = 80 A) did not. Based on this and on fluorescence resonance energy transfer experiments, we describe a dimeric binding mode in which two T cell receptors engage in an anti-parallel fashion two pMHC complexes facing each other with their constant domains. This binding mode allows integration of diverse low affinity interactions, which increases the overall binding and, hence, the sensitivity of antigen recognition. In proof of this, we demonstrated that pMHC dimers containing one agonist and one null ligand efficiently activate CTL, corroborating the importance of endogenous pMHC complexes in antigen recognition.Keywords:
Histocompatibility
Mixed lymphocyte reaction
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We have isolated clones of alloreactive T cells by soft agar cloning of primed responder cells contained in serially restimulated, mixed lymphocyte cultures. These clones recognize unique mixed lymphocyte reaction (MLR) stimulating determinants present on (C57B/6 X A/J)F1 (B6A) spleen cells. By assaying the reactivity patterns of these clones on a panel of stimulator cells, we have identified at least three separate "specificities" of alloreactive T cell clones. Several clones exhibiting one of these three reactivity patterns have been isolated on many occasions from different experiments. Using such clones of alloreactive T cells, we have identified and are attempting to define crossreactive MLR stimulating determinants exhibited by a panel of stimulator cells. Recognition by certain clones of a shared MLR determinant(s) on B6A and DBA/2 and of the lack of this determinant(s) on B6 stimulator cells questions current concepts concerning the nature of MLR stimulating determinants and T cell recognition of alloantigens.
Mixed lymphocyte reaction
Cloning (programming)
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H-2 antigens were discovered by Gorer (1936) as a blood group system associated with histocompatibility between mouse strains. Later research indicated that H-2 antigens were encoded by a series of genes, hence the designation H-2 complex (J. Klein, 1975). Similar complexes have been identified in all vertebrates examined (Götze, 1977) and are generally known as major histocompatibility complexes (MHC). It is now known that genes within the MHC influence as many as 60 separate traits (J. Klein, 1975, 1979) with many controlling important immunological functions.
Histocompatibility
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T cells upon activation with mitogens or autologous non T cells express surface HLA-DR antigens and are capable of stimulating autologous T cells in the autologous mixed lymphocyte reaction (T-T AMLR). We have examined T-TA AMLR, using T-non T AMLR activated-(TA) T cells as stimulators in young (21-32 yr) and aging humans (62-84 yr). In aging subjects a significantly (p less than 0 . 01) higher proliferative response was observed in T-TA AMLR as compared to simultaneously studied young subjects. In allogeneic MLR, no significant difference was observed between young and aging subjects. The increased T-TA AMLR could be a mechanism responsible for deficient T-non T AMLR reported in aging humans.
Mixed lymphocyte reaction
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Mixed lymphocyte reaction
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Murine monoclonal antibodies (MoAb) to distinct determinants of human Ia antigens and low doses of prednisone induce different effects on the autologous mixed lymphocyte reaction (MLR), stimulated by PHA-T cells or by non-T cells, and on allogeneic MLRs. These results suggest that distinct domains of Ia antigens and/or mechanisms are involved in these types of MLRs.
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Pan-T antigens
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Results of mixed lymphocyte culture reactions and tissue typing were correlated with the clinical courses of recipients of living related donor renal allografts. Forty-nine patients tested by the mixed lymphocyte culture technique were divided into two response groups: stimulation index greater than 5 and stimulation index less than 5. Seventy patients were tested by standard tissue typing methods and were categorized by the number of misstimulation in mixed lymphocyte culture than with mismatched antigens, suggesting that lymphocyte-defined histocompatibility is more important than serologically defined histocompatibility in selecting the best possible allograft donor.
Tissue typing
Histocompatibility
Mixed lymphocyte reaction
Histocompatibility Testing
Minor histocompatibility antigen
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A study of seven pig families enabled the identification of individuals who were homozygous for the gene products identified by the mixed lymphocyte reaction. Homozygotes were engaged as markers to elucidate histocompatibility phenotypes. Thus a system evolved in which histocompatibility phenotypes were assessed independently of serologically dependent techniques.
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Influence of the major histocompatibility comp(MHC) on the response to and expression of H‐Y in rats
Abstract The influence of the major histocompatibility complex (MHC) on the survival of H‐Y‐incompatible skin grafts in rats has been determined by challenging normal and previously sensitized females of various isogenic and congenic strains with male trunk or ear skin isografts. The MHC's influence on the potency of H‐Y has also been evaluated by determining the survival of male parental strain ear skin grafts on sensitized (with F 1 hybrid male cells) F 1 hybrid females of two different MHC congenic strains. The results indicate that, as in mice, the MHC has a dual affect on H‐Y; it is involved in determining the ability of females to respond to the antigen as well as influencing its potency.
Congenic
Histocompatibility
Mouse strain
Strain (injury)
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The influence of subregions of the canine major histocompatibility complex (MHC) on renal allograft survival is assessed in recipients without immunosuppressive therapy. Results in six beagle littermate donor-recipient pairs in which the donor or recipient had a recombination in the MHC are compatible with the concept of a predominant role for the subregion containing the major mixed lymphocyte reaction (MLR) locus in determining allograft survival. Results in unrelated mongrel dogs indicate that compatibility for MLR induces a longer kidney allograft survival than compatibility for the serologically defined (SD) antigens. However, the effect of combined matching for MLR and SD antigens in unrelated donor-recipient pairs is slight in comparison to the effect of MLR and/or SD matching in littermate-related dogs. This indicates that other important histocompatibility systems probably exist in this species.
Beagle
Histocompatibility
Mixed lymphocyte reaction
Histocompatibility Testing
Minor histocompatibility antigen
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